Calcific aortic valve disease is a growing health problem in our aging population. To overcome our limited understanding in the disease process and to develop therapeutic strategies beyond valve replacement, better animal models are critically needed. To date, most animal models have focused on hyperlipidemia-induced vascular inflammation. Our research laboratory focuses on the cytokine-like protein S100A12, which is not present in mice. The absence of S100A12 in mice could be one reason for an overall reduced amount of vascular inflammation seen in normolipidemic mice. We now developed a new humanized transgenic mouse with expression of human S100/calgranulins (S100A12, S100A8 and S100A9) in tissues that normally express these proteins by using the human S100 gene cluster with its endogenous regulatory elements. These mice are termed hBAC-S100 since a bacterial artificial chromosome was used to generate this model. These mice have a pro-inflammatory milieu and develop aortic valve disease with micro-calcification in a lipid neutral manner. In AIM 1 we would like to examine systemic and local inflammatory state in transgenic hBAC-S100 mice and study mechanisms by which S100/Calgranulins induce calcification of the aortic valve. In AIM 2 we would like to use the humanized S100/calgranulin mouse to develop new models of advanced calcific aortic valve disease by exposing these mice to additional vascular stressors, like hyperlipidemia and chronic kidney disease. It is our hypothesis that human S100A12 is a disease-modifying factor that accelerates calcific aortic valve disease in metabolically challenged mice by its pro-apoptotic effects on stressed cells. In our previous work we demonstrated vastly accelerated atherosclerosis and vascular calcification in transgenic mice with expression of human S100A12 targeted to the vascular smooth muscle and exposed to hyperlipidemia or chronic kidney disease. In AIM 3 we would like to test the hypothesis that limiting S100/calgranulin induced chronic inflammation by either preventing activation of its receptor RAGE or by impaired downstream signaling of the S100/RAGE axis will attenuate the progression of calcific aortic valve disease in vivo. Our research will contribute to a better understanding of the relationship of systemic and local aortic valve inflammation. Delineating the mechanisms by which S100/calgranulin regulates its effect on aortic valve remodeling will identify those steps that should be targeted for therapy. Our experiments will identify whether the S100/calgranulins/RAGE axis is a sufficient therapeutic target for aortic valve disease. (End of Abstract)